U.S. patent number 10,123,975 [Application Number 15/616,494] was granted by the patent office on 2018-11-13 for single solid oral dosage forms for treating helicobacter pylori infection and duodenal ulcer disease.
The grantee listed for this patent is Darren Rubin. Invention is credited to Darren Rubin.
United States Patent |
10,123,975 |
Rubin |
November 13, 2018 |
Single solid oral dosage forms for treating Helicobacter pylori
infection and duodenal ulcer disease
Abstract
The present invention provides improved pharmaceutical
formulations for the treatment of Helicobacter pylori infection and
duodenal ulcer disease, and includes methods of preparation and
methods of medicinal use of at least one proton pump inhibitor and
at least two different antibiotics within the same solid oral
dosage form, whereby at least one antibiotic is coated or
encapsulated independently from at least one other antibiotic
within this solid oral dosage form.
Inventors: |
Rubin; Darren (Largo, FL) |
Applicant: |
Name |
City |
State |
Country |
Type |
Rubin; Darren |
Largo |
FL |
US |
|
|
Family
ID: |
64050711 |
Appl.
No.: |
15/616,494 |
Filed: |
June 7, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
14463776 |
Aug 20, 2014 |
9700514 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
9/0053 (20130101); A61K 31/496 (20130101); A61K
31/341 (20130101); A61K 31/4164 (20130101); A61K
31/424 (20130101); A61K 31/431 (20130101); A61K
31/7048 (20130101); A61K 31/4439 (20130101); A61K
31/43 (20130101); A61K 9/4891 (20130101); A61K
31/426 (20130101) |
Current International
Class: |
A61K
9/48 (20060101); A61K 31/424 (20060101); A61K
31/7048 (20060101); A61K 31/4439 (20060101); A61K
9/00 (20060101); A61K 31/431 (20060101); A61K
31/496 (20060101); A61K 31/341 (20060101); A61K
31/4164 (20060101); A61K 31/43 (20060101); A61K
31/426 (20060101) |
Primary Examiner: Nielsen; Thor B
Parent Case Text
RELATED APPLICATION
The present application is a continuation-in-part of pending U.S.
patent application Ser. No. 14/463,776 filed Aug. 20, 2014, the
subject matter of which application is incorporated herein by
reference.
Claims
What is claimed is:
1. A method for treatment of patients with at least one of
Helicobacter pylori infection and duodenal ulcer disease, said
method comprising orally administering a solid oral dosage form at
least once per day for at least one week; said solid oral dosage
form consisting of a bismuth-free pharmaceutical formulation; said
bismuth-free pharmaceutical formulation consisting of one
enteric-coated proton pump inhibitor active pharmaceutical
ingredient wherein the one enteric-coated proton pump inhibitor is
optionally in the form of enteric-coated granules or enteric-coated
pellets within same said oral dosage form; one histamine
H2-receptor antagonist active pharmaceutical ingredient, or a
combination thereof; said bismuth-free pharmaceutical formulation
further consisting of at least one pharmaceutically acceptable
excipient ingredient and at least two different antibiotic active
pharmaceutical ingredients, wherein said at least two different
antibiotic active pharmaceutical ingredients are selected from the
group consisting of macrolide antibiotics and beta-lactam
antibiotics and wherein at least one of said at least two different
antibiotic active pharmaceutical ingredients is coated independent
from, and protected from contact or interacting with, at least one
other antibiotic active pharmaceutical ingredient of said
bismuth-free pharmaceutical formulation at least before said orally
administering said solid oral dosage form and wherein the solid
oral dosage form optionally further consists of at least one
beta-lactamase inhibitor and optionally wherein all active
pharmaceutical ingredients are protected from contact and
interacting with each other within same said solid oral dosage
form.
2. The method of claim 1 wherein said at least one pharmaceutically
acceptable excipient ingredient is selected from the group
consisting of antiadherents, binders, coatings, capsule
shell-comprising excipients, nanoparticles, chelators, buffering
agents, acid reacting excipients, alkaline reacting excipients,
disintegrants, fillers, diluents, colors, lubricants, glidants,
preservatives, sorbents, flavors, sweeteners, carriers, solvents,
surfactants, and any mixtures and combinations thereof.
3. The method of claim 1 wherein said one enteric-coated proton
pump inhibitor active pharmaceutical ingredient is selected from
the group consisting of lansoprazole, omeprazole, omeprazole
magnesium, aripiprazole, dexlansoprazole, esomeprazole,
esomeprazole magnesium, esomeprazole sodium, esomeprazole
strontium, pantoprazole, pantoprazole sodium, rabeprazole,
rabeprazole sodium, and any salts, solvates, polymorphs, racemic
mixtures and enantiomers thereof.
4. The method of claim 1 wherein said at least two different
antibiotic active pharmaceutical ingredients are selected from the
group consisting of clarithromycin, erthythromycin, azithromycin,
dirithromycin, roxithromycin, telithromycin, carbomycin A,
josamycin, kitasamycin, midecamycin, oleandomycin, solithromycin,
spiramycin, troleandomycin; penicillin drugs, amoxicillin,
ampicillin, talampicillin, bacampicillin, lenampicillin,
mezlocillin, sultamicillin, temocillin; and any salts, solvates,
polymorphs, racemic mixtures and enantiomers, mixtures and
combinations thereof.
5. The method of claim 1 wherein at least one of said at least two
different antibiotic active pharmaceutical ingredients is replaced
by or supplemented with a fluoroquinolone antibiotic or
tetracycline antibiotic.
6. The method of claim 1 wherein the at least one beta-lactamase
inhibitor is selected from the group consisting of clavulanic acid,
tazobactam, sulbactam, and any salts, solvates, polymorphs, racemic
mixtures and, enantiomers, mixtures and combinations thereof.
7. The method of claim 1 further comprising a step of
pharmacogenomic testing of drug metabolism enzymes of said patients
prior to said orally administering said solid oral dosage form.
8. The method of claim 1 wherein said one histamine H2-receptor
antagonist is selected from the group consisting of ranitidine,
cimetidine, famotidine, nizatidine, and any salts, solvates,
polymorphs, racemic mixtures and enantiomers thereof.
9. The method of claim 1 wherein said solid oral dosage form
consists of a single tablet or single capsule structure.
10. The method of claim 1 wherein said solid oral dosage form
consists of at least two identical capsules or tablets.
11. The method of claim 1 wherein said solid oral dosage form
consists of three to eight identical capsules or tablets.
12. The method of claim 1 wherein said orally administering said
solid oral dosage form is at least twice per day for up to three
weeks.
13. The method of claim 1 wherein said orally administering said
solid oral dosage form is twice per day for two weeks.
14. The method of claim 1 wherein said orally administering said
solid oral dosage form is twice per day for less than two
weeks.
15. The method of claim 1 further comprising a step of
gastrointestinal endoscopy prior to beginning said orally
administering said solid oral dosage form to identify Helicobacter
pylori infection or duodenal ulcer disease.
16. The method of claim 1 further comprising a step of
gastrointestinal endoscopy after completing said orally
administering said solid oral dosage form to confirm elimination of
Helicobacter pylori infection.
17. The method of claim 1 wherein said duodenal ulcer disease is
active or was active within the past twelve months.
18. The method of claim 1 further comprising a step of orally
administering an antibiotic-free pharmaceutical preparation
consisting of proton pump inhibitor active pharmaceutical
ingredient, histamine H2-receptor antagonist active pharmaceutical
ingredient, bismuth-containing active pharmaceutical ingredient, or
a combination thereof after completing all said orally
administering of said solid oral dosage form.
19. The method of claim 1 wherein said at least one of said at
least two different antibiotic active pharmaceutical ingredients is
coated independently from said at least one other antibiotic active
pharmaceutical ingredient of said at least two different antibiotic
active ingredients in order to have at least one of improved
stability, longer shelf-life, maintained potency, less impurities,
lower toxicity, or a combination thereof.
20. The method of claim 1 wherein said at least one of said at
least two different antibiotic active pharmaceutical ingredients is
coated independently from said at least one other antibiotic active
pharmaceutical ingredient of said at least two different antibiotic
active ingredients in order to have a different release rate.
21. The method of claim 1 wherein said at least one of said at
least two different antibiotic active pharmaceutical ingredients is
coated independently from said at least one other antibiotic active
pharmaceutical ingredient of said at least two different antibiotic
active ingredients; a structure, dimensions, and composition of
said independent coating within same said solid oral dosage form
chosen according to the metabolizing needs/metabolizing enzyme
polymorphisms of a patient/patient group in order to provide a
release rate and onset of bioavailability directly proportionate to
the extent of metabolic efficiency of said patient/patient group
with a faster release and onset of bioavailability of said at least
one of said at least two different antibiotic active pharmaceutical
ingredients for heterozygous extensive metabolizers than for poor
metabolizers, and with a faster release and onset of
bioavailability of said at least one of said at least two different
antibiotic active pharmaceutical ingredients for homozygous
extensive metabolizers than for heterozygous extensive
metabolizers.
22. A method for the treatment of patients with at least one of
Helicobacter pylori infection and duodenal ulcer disease, said
method comprising orally administering a solid oral dosage form at
least once per day for at least one week; said solid oral dosage
form consisting of two to eight identical capsules or tablets that
are bismuth-free, said two to eight identical capsules or tablets
consisting of one enteric-coated proton pump inhibitor active
pharmaceutical ingredient, one histamine H2-receptor antagonist
active pharmaceutical ingredient, or a combination thereof; said
two to eight identical capsules or tablets further consisting of at
least one pharmaceutically acceptable excipient ingredient, and at
least two different antibiotic active pharmaceutical ingredients,
wherein said at least two different antibiotic active
pharmaceutical ingredients are selected from macrolide antibiotics
and beta-lactam antibiotics and wherein at least one of said at
least two different antibiotic active pharmaceutical ingredient is
protected from contact or interacting with at least one other
antibiotic active pharmaceutical ingredient at least before said
orally administering said solid oral dosage form by being coated
independent from said at least one other antibiotic active
pharmaceutical ingredient of said at least two different antibiotic
active ingredients within each of said two to eight identical
capsules or tablets and optionally wherein said one enteric-coated
proton pump inhibitor active pharmaceutical ingredient is in the
form of coated granules, coated pellets, or a combination
thereof.
23. The method of claim 22 wherein said one enteric-coated proton
pump inhibitor active pharmaceutical ingredient is in the form of
coated granules, coated pellets, or a combination thereof and
selected from the group consisting of lansoprazole,
dexlansoprazole, omeprazole, aripiprazole, esomeprazole,
pantoprazole, and rabeprazole, said one enteric-coated proton pump
inhibitor active pharmaceutical ingredient is in the amount of 10
mg to 60 mg in said solid oral dosage form; and said one histamine
H2-receptor antagonist is selected from the group consisting of
ranitidine, cimetidine, and nizatidine in the amount of 150 mg to
800 mg or famotidine in the amount of 20 mg to 40 mg, in said solid
oral dosage form.
24. A method for the treatment of patients with at least one of
Helicobacter pylori infection and duodenal ulcer disease, said
method comprising orally administering a solid oral dosage form
twice per day for one to two weeks; said solid oral dosage form
consisting of two to six identical single capsules that are
bismuth-free, said two to six identical single capsules consisting
of one enteric-coated proton pump inhibitor active pharmaceutical
ingredient, wherein said one enteric-coated proton pump inhibitor
active pharmaceutical ingredient is selected from lansoprazole,
dexlansoprazole, and omeprazole in an amount of 20 mg to 30 mg in
said solid oral dosage form; said two to six identical single
capsules further consisting of at least one pharmaceutically
acceptable excipient ingredient, and at least two different
antibiotic active pharmaceutical ingredients; wherein at least one
of said at least two different antibiotic active pharmaceutical
ingredient is protected from contact or interacting with at least
one other antibiotic active pharmaceutical ingredient at least
before said orally administering said solid oral dosage form by
being coated independent from said at least one other antibiotic
active pharmaceutical ingredient of said at least two different
antibiotic active ingredients within each of said two to six
identical single capsules, said at least two different antibiotic
active pharmaceutical ingredients consisting of amoxicillin and
clarithromycin each in an amount of at least 500 mg in said solid
oral dosage form.
25. A method for the treatment of patients with at least one of
Helicobacter pylori infection and duodenal ulcer disease, said
method comprising orally administering a solid oral dosage form at
least once per day for at least one week; said solid oral dosage
form consisting of two to eight identical single capsules or
tablets that are bismuth-free; said two to eight identical single
capsules or tablets consisting of one enteric-coated proton pump
inhibitor active pharmaceutical ingredient in the form of coated
granules, coated pellets, or a combination thereof, one histamine
H2-receptor antagonist active pharmaceutical ingredient, or a
combination thereof; said two to eight identical single capsules or
tablets further consisting of at least one pharmaceutically
acceptable excipient ingredient and at least two different
antibiotic active pharmaceutical ingredients; wherein said at least
two different antibiotic active pharmaceutical ingredients are
selected from the group consisting of macrolide antibiotics and
beta-lactam antibiotics and wherein at least one of said at least
two different antibiotic active pharmaceutical ingredients is
protected from contact or interacting with at least one other
antibiotic active pharmaceutical ingredient at least before said
orally administering said solid oral dosage form by being coated
independent from said at least one other antibiotic active
pharmaceutical ingredient within each of said two to eight
identical single capsules or tablets in order to have at least one
of a different release rate, improved stability, longer shelf-life,
maintained potency, less impurities, lower toxicity, or a
combination thereof; a coated form of said at least one of said at
least two different antibiotic active pharmaceutical ingredients
having a structure, dimensions, and composition chosen according to
the metabolizing needs/metabolizing enzyme polymorphisms of a
patient/patient group in order to provide a release rate and onset
of bioavailability directly proportionate to the extent of
metabolic efficiency of said patient/patient group with a faster
release and onset of bioavailability of said at least one of said
at least two different antibiotic active pharmaceutical ingredients
for heterozygous extensive metabolizers than for poor metabolizers,
and with a faster release and onset of bioavailability of said at
least one of said at least two different antibiotic active
pharmaceutical ingredients for homozygous extensive metabolizers
than for heterozygous extensive metabolizers; and wherein all
active pharmaceutical ingredients are protected from contact and
interacting with each other within same said solid oral dosage
form.
26. The method of claim 25 wherein said one enteric-coated proton
pump inhibitor active pharmaceutical ingredient in the form of
coated granules, coated pellets, or a combination thereof is
selected from the group consisting of lansoprazole,
dexlansoprazole, and omeprazole in an amount of 20 mg to 30 mg in
said solid oral dosage form, and said at least two different
antibiotic active pharmaceutical ingredients consists of
amoxicillin and clarithromycin each in an amount of at least 500 mg
in said solid oral dosage form, wherein at least clarithromycin is
in coated form in said solid oral dosage form.
Description
FIELD OF THE INVENTION
The present invention provides improved pharmaceutical formulations
for the treatment of Helicobacter pylori infection and duodenal
ulcer disease, and includes methods of preparation and methods of
medicinal use of at least one proton pump inhibitor and at least
two different antibiotics within the same solid oral dosage form,
whereby at least one antibiotic is coated or encapsulated
independently from at least one other antibiotic within this solid
oral dosage form.
BACKGROUND OF THE INVENTION
Helicobacter pylori is a spiral-shaped, Gram-negative,
microaerophilic bacterium found in the stomach and upper
gastrointestinal tract of perhaps more than half of the world's
population. Many with this infection are asymptomatic, yet
Helicobacter pylori can cause chronic gastritis in children and
adults, and is associated with an increased risk of developing
gastric cancer and mucosal-associated-lymphoid-type (MALT)
lymphoma. Unbeknownst to the medical community for many years, this
bacterium was responsible for most cases of duodenal and peptic
ulcers. These ulcers are associated with pain, indigestion, nausea,
and loss of appetite. Bleeding from these ulcers could cause
fatigue from anemia, and blood may show up in the vomit and stool.
Before this bacterium was discovered, gastric and intestinal ulcers
were thought to be caused mainly by spicy foods, stress, and
excessive stomach acid secretion. Patients were given long-term
medications, such as histamine H2-receptor antagonists
(H2-blockers) and proton pump inhibitors, without a chance for
permanent cure. Although these medications relieve ulcer-related
symptoms, heal gastric mucosal inflammation, and may heal the
ulcer, H2-blockers and proton pump inhibitors do not treat the
infection and ulcers often reoccur, especially when acid
suppression is removed. Only antibiotics have the potential to cure
a Helicobacter pylori infection and prevent ulcer reoccurrence. It
is believed that once this bacterium is eliminated, so is the
chronic inflammation in the walls of the stomach and intestine that
make these tissues more vulnerable to damage caused by digestive
juices. Importantly, it was found that higher levels of acid
suppression achieved with a proton pump inhibitor could potentiate
the activity of antibiotics used to eradicate Helicobacter pylori
infection. Modern regimens of eradicating Helicobacter pylori
infection therefore include a proton pump inhibitor and
antibiotics.
Proton pump inhibitors suppress stomach acid secretion by
inhibiting or irreversibly blocking the hydrogen/potassium
adenosine triphosphatase enzyme system of the gastric parietal
cells to prevent the secretion of hydrogen ions. This mechanism of
action is different from that of H2-blockers, which block the
action of histamine on the histamine H2-receptors of parietal cells
to decrease their production of acid. The proton pump inhibitor is
often provided as a tablet or capsule, often containing delayed
release, enteric-coated granules that survive the low pH of the
stomach, and release at higher pH in the intestines, as proton pump
inhibitors are acid labile. In the more neutral condition of the
small intestines, the proton pump inhibitor is rapidly absorbed
into the bloodstream. The strength of the proton pump inhibitor
usually ranges from 10 mg to 60 mg, and is often taken 1 to 2 times
per day. Lansoprazole and omeprazole are the most commonly
prescribed proton pump inhibitors, although other proton pump
inhibitors include aripiprazole, dexlansoprazole, esomeprazole,
pantoprazole, and rabeprazole. While many proton pump inhibitors
are benzimidazole derivatives, newer proton pump inhibitors include
imidazopyridine derivatives. Proton pump inhibitors, such as
lansoprazole, often have inter-individual and intra-individual
differences in pharmacokinetic profiles and can be affected by
differences in cytochrome P450 enzyme genotypes; polymorphisms
including those of CYP2C19 and CYP3A.
Antibiotics are given concomitantly with the proton pump inhibitor
during Helicobacter pylori eradication therapy. At least two
different antibiotics are recommended as part of Helicobacter
pylori eradication therapy to reduce the risk of treatment failure
and antibiotic resistance. The most commonly prescribed
Helicobacter pylori triple therapy includes amoxicillin,
clarithromycin, and either lansoprazole or omeprazole, each as a
separate, individual tablet or capsule. Amoxicillin is a broad
antimicrobial beta-lactam that inhibits the synthesis of the
bacterial cell wall in replicating bacteria. Amoxicillin is
bactericidal for both gram-positive and gram-negative bacteria and
is destroyed by beta-lactamase produced from both types of
bacteria. Clarithromycin is an advanced-generation macrolide
antibiotic with a broad in vitro antimicrobial spectrum. It
interferes with protein synthesis in bacteria. Clarithromycin is
rapidly and nearly completely absorbed from the gastrointestinal
tract and has extensive diffusion in the tissues and bodily fluids.
It forms a microbiologically active primary metabolite,
14-(R)-hydroxyclarithromycin, primarily by the cytochrome,
CYP3A.
If a patient is believed to be resistant to clarithromycin, an
alternative antibiotic may be prescribed, such as tetracycline.
Tetracycline is another broad-spectrum polyketide antibiotic that
inhibits protein synthesis in bacteria. Metronidazole is a
nitroimidazole antibiotic that inhibits nucleic acid synthesis
primarily in anaerobic bacteria. However, metronidazole is less
used, perhaps because it appears to be somewhat mutagenic and
carcinogenic.
The Helicobacter pylori triple therapy regimen generally lasts for
7 to 14 days, and is preferably 10 or 14 days. It is very common
for a physician to prescribe 500 mg amoxicillin capsules, 500 mg
clarithromycin tablets, and 30 mg lansoprazole or 20 mg omeprazole
delayed-release capsules as a triple therapy. These regimens
include taking two amoxicillin 500 mg capsules, one 500 mg
clarithromycin tablet, and one 30 mg lansoprazole or 20 mg
omeprazole delayed-release capsule, administered together twice
daily (in the morning and evening) for 10 or 14 days. These
therapies therefore comprise eight pills per day, four in the
morning and four in the evening. These pills come from 3 different
prescription bottles. To provide greater convenience to physicians
and patients, convenience kits, daily blister cards containing
morning and night doses of these pills, have been produced. Still,
these convenience kits contain 3 different pills of active
ingredients, and there is some risk of accidentally taking one or
more pills from the evening dose when taking pills from the morning
dose, and vice versa. Moreover, the taking of 8 pills per day (112
pills over 2 weeks) for the triple therapy, not to mention if the
patient is taking other medications, is a great number of pills
that can lead to poor patient compliance or distress. Some patients
have a gag reflex and have trouble swallowing pills.
There exists a great need for an improved Helicobacter pylori
eradication therapy that solves the problems inherent in prior
Helicobacter pylori eradication therapies; namely poor compliance,
patient distress and confusion among a great number of different
pills, which may also lead to medication dosing errors and
increased side effects. The present invention fulfills this need by
providing at least one proton pump inhibitor active pharmaceutical
ingredient, and at least two different antibiotic active
pharmaceutical ingredients, in the same solid oral dosage form. The
present invention provides the advantage of greatly reducing the
number of pills administered in a Helicobacter pylori eradication
regimen. Preferably, only 1 to 3 of these pills are taken in the
morning and evening, for a preferable total of 2 to 6 pills taken
per day, thus greatly improving patient compliance in a regimen
lasting up to 14 days. Since each of these pills are identical, a
single bottle can contain them to avoid confusion and medication
errors. The present invention also provides new formulations and
methods of improving stability of these active pharmaceutical
ingredients, thereby assuring the identity, strength, quality,
purity, potency, and safety of the solid dose drug product of the
invention. At least one antibiotic active pharmaceutical ingredient
is encapsulated independently from at least one other antibiotic
active pharmaceutical ingredient within the same solid oral dosage
form. The present invention improves the standard of patient care
in Helicobacter pylori eradication therapy and provides therapies
ideally suited for the different metabolic needs of patients.
DETAILED DESCRIPTION OF THE INVENTION
Past regimens of Helicobacter pylori eradication therapy consist of
numerous different pills taken orally for up to 14 days, e.g., a
total of 112 pills in 2 weeks, which causes inconvenience,
distress, and poor patient compliance. The present invention
provides new formulations of Helicobacter pylori eradication
therapy in a single solid oral dosage form, along with methods of
preparation and methods of medical use, which greatly reduces the
total number of pills taken (e.g., by one-half to one-quarter)
while maintaining efficacy.
In its preferred embodiment, the invention is a solid oral dosage
form for the treatment of patients with at least one of
Helicobacter pylori infection and/or duodenal ulcer disease. The
duodenal ulcer disease can be active or can be recent; e.g., the
patient can have a one-year history of a duodenal ulcer. This
invention can also be used for patients suspected of having an
Helicobacter pylori infection without confirmation. This invention
can also be used for patients having ailments other than duodenal
ulcer disease caused by an Helicobacter pylori infection. The said
solid oral dosage form includes at least one proton pump inhibitor
active pharmaceutical ingredient and at least two different
antibiotic active pharmaceutical ingredients. The solid oral dosage
form further includes at least one pharmaceutically acceptable
excipient ingredient. Embodiments of this invention can include any
number of excipient ingredients and/or percent weight/weight of
these excipient ingredients. Excipient ingredients are selected
from the classes of excipients including, but not limited to,
antiadherents, binders, coatings, capsule shell-comprising
excipients, nanoparticles, chelators, buffering agents, acid
reacting excipients, alkaline reacting excipients, disintegrants,
fillers, diluents, colors, lubricants, glidants, preservatives,
sorbents, flavors, sweeteners, carriers, solvents, surfactants, and
any mixtures and combinations thereof; and can include lipids,
liposomes, glycoproteins, proteins, carbohydrates, starches, waxes,
and polymers.
The at least one proton pump inhibitor active pharmaceutical
ingredient is selected from the class of proton pump inhibitors
including, but not limited to, lansoprazole, omeprazole, omeprazole
magnesium, aripiprazole, dexlansoprazole, esomeprazole,
esomeprazole magnesium, esomeprazole sodium, esomeprazole
strontium, pantoprazole, pantoprazole sodium, rabeprazole,
rabeprazole sodium, and any salts, solvates, polymorphs, racemic
mixtures, enantiomers, derivatives, mixtures and combinations
thereof. The at least one proton pump inhibitor can therefore be a
benzimidazole derivative or a imidazopyridine derivative. The at
least one proton pump inhibitor active pharmaceutical ingredient is
preferably included in enteric-coated pellets and/or enteric-coated
granules within same said solid oral dosage form. Most proton pump
inhibitors are labile in stomach acid, so the enteric-coating of
their granules/pellets ensures release at the higher, more neutral
pH of the intestines where the proton pump inhibitor is rapidly
absorbed. In order to provide enteric-coated granules or pellets of
proton pump inhibitor, the solid oral dosage form further includes
at least one pharmaceutically acceptable excipient ingredient
comprising the enteric coating, and is commonly an acrylic-polymer
coating of some type. The following are nonlimiting examples of
enteric-coated granules and pellets of proton pump inhibitor. These
examples can optionally include alkaline reacting compounds as
excipients in the active ingredient core or active ingredient layer
that can help stabilize the proton pump inhibitor and/or help with
its release.
A nonlimiting example of ingredients used in a formulation of
enteric-coated granules or pellets of proton pump inhibitor include
lansoprazole and/or omeprazole active pharmaceutical ingredient and
the excipient ingredients: crospovidone, hypromellose, lactose,
magnesium stearate, mannitol, meglumine, methacrylic acid
copolymer, poloxamer, povidone and triethyl acetate. The
methacrylic acid copolymer serves as the enteric-coating
surrounding the inner core comprised of at least one proton pump
inhibitor active pharmaceutical ingredient (e.g., lansoprazole
and/or omeprazole) and the other excipients. There is preferably a
separating layer between the inner core and enteric coating.
Another nonlimiting example of ingredients used in a formulation of
enteric-coated granules or pellets of proton pump inhibitor include
lansoprazole and/or omeprazole active pharmaceutical ingredient and
the excipient ingredients: hydroxypropyl cellulose, low substituted
hydroxypropyl cellulose, colloidal silicon dioxide, magnesium
carbonate, methacrylic acid copolymer, starch, talc, sugar sphere,
sucrose, polyethylene glycol, polysorbate 80, and titanium dioxide.
The enteric coated pellets are preferably multi-layered or
multi-coated starting from the small sugar sphere that serves as a
small sugar bead or seed. Each layer or coat is generally applied
as a solution of ingredients and solvent in the form of a mist from
which the solvent evaporates or is dried off, thereby, leaving the
ingredients behind on the sphere. Starting from the center is the
tiny, sugar-containing bead core (e.g., a small sugar bead);
followed by a separating layer or coat that can include
hydroxypropyl cellulose; a drug loaded layer or coat including at
least one proton pump inhibitor active pharmaceutical ingredient
(e.g., lansoprazole and/or omeprazole) and at least one
pharmaceutically acceptable excipient ingredient (e.g., a binding
agent, etc.); another separating layer or coat that can include
hydroxypropyl cellulose; and an enteric coating layer that can
include an acrylic coating (e.g., methacrylic acid copolymer).
The at least two different antibiotic active pharmaceutical
ingredients (biocides) of the invention are selected from the
classes of antibiotics including, but not limited to, polyketide
antibiotics; macrolide antibiotics, including, but not limited to,
clarithromycin, erthythromycin, azithromycin, dirithromycin,
roxithromycin, telithromycin, carbomycin A, josamycin, kitasamycin,
midecamycin, oleandomycin, solithromycin, spiramycin,
troleandomycin; beta-lactam antibiotics; penicillin drugs
including, but not limited to amoxicillin, ampicillin,
talampicillin, bacampicillin, lenampicillin, mezlocillin,
sultamicillin, temocillin; cephem/cephalosporin antibiotics
including, but not limited to, cefaclor, cefadroxil, cefalexin,
cefpodoxime proxetil, cefixime, cefdinir, ceftibuten, cefotiam
hexetyl, cefetamet pivoxil, cefuroxime axetil; penem antibiotics
including, but not limited to, faropenem, ritipenem; monobactam
antibiotics; sulfonamide antibiotics; lincosamide antibiotics
including, but not limited to, lincomycin or clindamycin;
aminoglycoside antibiotics including, but not limited to
paromomycin; tetracycline antibiotics including, but not limited
to, tetracycline, minocycline, doxycycline; quinolone antibiotics
including fluoroquinolone antibiotics, but not limited to,
ofloxacin, levofloxacin, norfloxacin, enoxacin, ciprofloxacin,
lomefloxacin, tosufloxacin, fleroxacin, sparfloxacin, temafloxacin,
nadifloxacin, grepafloxacin, baloflaxacin, prulifloxacin,
pazufloxacin; nitroimidazole antibiotics including, but not limited
to, metronidazole, tinidazole; nitrofuran antibiotics including,
but not limited to, nitrofurantoin, furazolidone, nifurtoinol;
rifamycin antibiotics including, but not limited to, rifampicin,
rifabutin, rifapentine, rifaximin; glycopeptide antibiotics
including, but not limited to ramoplanin; and any salts, solvates,
polymorphs, racemic mixtures, enantiomers, derivatives, mixtures
and combinations thereof. Although most antibiotics effective
against Gram-negative bacteria, e.g., Helicobacter pylori, can be
used, the at least two different antibiotic active pharmaceutical
ingredients preferably include amoxicillin and clarithromycin
and/or tetracycline. Metronidazole may also be used or substituted
for one of these preferred antibiotic active pharmaceutical
ingredients.
Some antibiotics are known to affect the pharmacokinetics of proton
pump inhibitors, and vice versa, especially in patients known as
poor metabolizers based on their polymorphs of certain cytochrome
P450 enzymes, such as CYP3A. This is true of clarithromycin and
lansoprazole whose metabolisms involve CYP3A. Doses of
clarithromycin and lansoprazole can slow their own metabolism and
the metabolism of each other, and may negatively affect their
bioavailability; whereas, the pharmacokinetics of amoxicillin is
affected much less, if at all, by these other active pharmaceutical
ingredients. While a patient's age may have little influence on the
pharmacokinetics of amoxicillin, patient's age can influence the
pharmacokinetics of lansoprazole and clarithromycin.
It was decided to experiment with different solid dosage forms
containing proton pump inhibitor and different antibiotics by
encapsulating independently at least one antibiotic in the same
solid oral dosage form also containing at least one proton pump
inhibitor and at least one additional antibiotic. The goal of these
experiments was to vary the independent encapsulation of at least
one antibiotic ingredient in the solid oral dosage form to vary the
release time and bioavailability of that antibiotic (e.g.,
clarithromycin), with respect to the other active ingredients
(e.g., lansoprazole and amoxicillin) and with respect to the
characteristics of certain patients. For instance, the release rate
of clarithromycin may be chosen as faster for homozygous extensive
metabolizers than for heterozygous extensive metabolizers, and
chosen as delayed for poor metabolizers and older patients and
those with renal impairment. In this manner the pharmacokinetics or
bioavailability of that antibiotic, and its pharmacokinetic
interactions with other active ingredients, can be modulated and
customized for different patient groups, and provide additional
different functions than Helicobacter pylori eradication therapy
convenience kits. There is currently no Helicobacter pylori
eradication therapy available with the elements of a proton pump
inhibitor and antibiotics in the same pill, nor the element of an
independently encapsulated antibiotic ingredient in the same pill.
There is currently no Helicobacter pylori eradication therapy that
can be tailored to a patient's drug metabolizing enzymes. The
perceived benefits of this solid oral dosage form would take place
after oral administration.
However, the independent encapsulation of at least one antibiotic
ingredient in the solid oral dosage form needed for these
experiments had unexpected benefits unrelated to the goal of these
experiments; unexpected benefits that occurred before oral
administration. It was inadvertently found that by encapsulating at
least one antibiotic ingredient in the solid oral dosage form
(e.g., clarithromycin) independently from other (antibiotic) active
ingredients, the stability of the formulation was greatly enhanced
over formulations that did not have this independent encapsulation
within the solid oral dosage form. These unexpected results can
provide for longer shelf-life for this improved Helicobacter pylori
eradication therapy, with lower impurities/degradants over this
shelf-life. It appears that this independent encapsulation may
provide protection against chemical reaction with other active
pharmaceutical ingredients (e.g., amoxicillin), such as with one or
more active moieties (e.g., amino, hydroxy, carbonyl and carboxyl
groups, etc.), which can otherwise lead to the formation of impure
intermediates that have little or no pharmacological activity or
may be toxic. This independent encapsulation may also help protect
against other factors including oxidation, residual organic
solvents and moisture, to improve stability of one or more active
ingredients of the solid oral dosage form. Due to the technical
challenges of independently encapsulating the at least one
antibiotic ingredient in the solid oral dosage form of this
Helicobacter pylori eradication therapy, production costs are
increased and more complex manufacturing machinery are required,
and this would not be obvious for one of ordinary skill in the art
to try.
The discovery of improved stability of these active pharmaceutical
ingredients helps assure the identity, strength, quality, purity,
potency, and safety of the solid dose drug product of the
invention.
The solid oral dosage form includes a structure selected from the
class of solid oral dosage forms including, but not limited to,
capsules, tablets, coated capsules, coated tablets, multi-coated
capsules, multi-coated tablets, multi-compartment capsules,
segmented capsules, multi-compartment tablets, segmented tablets,
multi-layer tablets, capsules with sub-capsule(s), capsules or
tablets with sub-tablet(s), and any combinations or derivatives
thereof. Coatings can include enteric coatings and non-enteric
coatings. A nonlimiting example of excipients that can comprise a
capsule shell include: gelatin, titanium dioxide, silicon dioxide,
iron oxide, sodium lauryl sulfate, and dyes, such as FD&C Blue
No. 1, FD&C Red No. 40, and FD&C Yellow No. 6. A
nonlimiting example of excipients that can comprise capsule fillers
are cellulose microcrystalline and magnesium stearate. A
nonlimiting example of excipients that can comprise tablet fillers
include: hypromellose, hydroxypropyl cellulose, colloidal silicon
dioxide, croscarmellose sodium, magnesium stearate,
microcrystalline cellulose, and povidone. A nonlimiting example of
excipients that can comprise a tablet coat include: propylene
glycol, sorbic acid, sorbitan monooleate, titanium dioxide,
vanillin, and D&C Yellow No. 10.
According to the invention, the solid oral dosage form includes at
least one proton pump inhibitor active pharmaceutical ingredient
and at least two different antibiotic active pharmaceutical
ingredients. At least one of said at least two different antibiotic
active pharmaceutical ingredients is encapsulated independently
from said at least one other antibiotic active pharmaceutical
ingredient of said at least two different antibiotic active
ingredients preferably in at least one separate sub-compartment,
segment, layer, sub-capsule, coated sub-tablet/large pellet or
coated granule/pellet within same said solid oral dosage form.
The following preferred embodiment examples of a solid oral dosage
form include up to 15 mg of lansoprazole and/or up to 10 mg of
omeprazole, up to 250 mg clarithromycin, and up to 500 mg
amoxicillin, per capsule or tablet. The following preferred
embodiment examples also include pharmaceutically acceptable
excipient ingredients. A Helicobacter pylori eradication therapy
according to these examples would consist of the administration of
two such solid oral dosages in the morning and evening for 7 to 14
days. Proton pump inhibitors other than lansoprazole and/or
omeprazole, and antibiotics other than clarithromycin and/or
amoxicillin, can be substituted in these preferred embodiments so
that these preferred embodiment examples are not meant to be
limiting. For instance, clarithromycin may be replaced by a
fluoroquinolone antibiotic or tetracycline antibiotic. The quantity
or dose of each active pharmaceutical ingredient is also not meant
to be limiting, and can vary according to the patient type, as can
one or more of the excipient ingredients and their quantities.
In a first preferred embodiment, this solid oral dosage form
includes the structure of a capsule containing coated agglomerates
(e.g., coated granules and/or coated pellets) of clarithromycin,
enteric-coated proton pump inhibitor granules (e.g., lansoprazole
and/or omeprazole), and amoxicillin powder and/or compact flakes or
granules or agglomerates of amoxicillin. The coated agglomerates
(e.g., coated granules and/or coated pellets) of clarithromycin are
preferably coated with a polymer. This polymer can be
acrylic-based, including, but not limited to, methacrylic acid
copolymer. Alternatively, this coating can include a pharmaceutical
glaze (e.g., a shellac coating) instead of or in addition to a
polymer. The desired coating excipients of the clarithromycin
coated granules or coated pellets are chosen such that
clarithromycin is protected from reacting with amoxicillin, and may
also be chosen to control the release of clarithromycin for
different patient metabolizers. The coated pellets of
clarithromycin are preferably multi-layered or multi-coated
starting from a small sugar sphere that serves as a small sugar
bead or seed. Each layer or coat is generally applied as a solution
of ingredients and solvent in the form of a mist from which the
solvent evaporates or is dried off, thereby, leaving the
ingredients behind on the sphere. Starting from the center is the
tiny, sugar-containing bead core (e.g., a small sugar bead);
followed by a separating layer or coat that can include
hydroxypropyl cellulose; the clarithromycin loaded layer or coat
including at least one pharmaceutically acceptable excipient
ingredient (e.g., a binding agent, etc.); another separating layer
or coat that can include hydroxypropyl cellulose; and the final
protective coating layer that can include an acrylic-based coating
(e.g., methacrylic acid copolymer) and/or a shellac coating.
Alternatively, the coated clarithromycin pellet can be a
clarithromycin-containing core with excipients surrounded by a
separating layer, followed by the protective outer coating layer.
These examples of how the coated clarithromycin pellet is
structured are not meant to be limiting.
In most embodiments of the invention, at least one of the
antibiotics is coated or encapsulated independent of the other
antibiotic. This can include a single coating around all of that
antibiotic in powder form or a single coating around agglomerates
of that antibiotic. The agglomerates of that antibiotic are
preferably coated as well. One aspect of this is to separate and
prevent contact and interaction of that antibiotic with that of
other antibiotic(s) in said solid oral dosage form. Preferably, all
active ingredients are protected from contact and interaction with
each other in said solid oral dosage form.
In an alternate first preferred embodiment, the amoxicillin is also
in the form of coated pellets, so that the capsule includes coated
pellets of amoxicillin, coated pellets of clarithromycin, and
coated pellets of lansoprazole and/or omeprazole. These active
ingredient are all protected from interacting with each other by
means of their own protective coatings; i.e., all said active
pharmaceutical ingredients are encapsulated independently from each
other within same said solid oral dosage form.
In a second preferred embodiment, the solid oral dosage form
includes the structure of a capsule. The contents interior to the
capsule shell include amoxicillin powder and/or compact flakes,
enteric-coated proton pump inhibitor granules (e.g., lansoprazole
and/or omeprazole), and a sub-capsule containing clarithromycin. In
an alternate second preferred embodiment, the capsule includes
clarithromycin powder and/or compact flakes, enteric-coated proton
pump inhibitor granules (e.g., lansoprazole and/or omeprazole), and
a sub-capsule containing amoxicillin. In another alternate second
preferred embodiment, this capsule includes enteric-coated proton
pump inhibitor granules (e.g., lansoprazole and/or omeprazole), a
sub-capsule containing clarithromycin, and a sub-capsule containing
amoxicillin. The antibiotics of a sub-capsule can be in powder,
agglomerate, solid, colloidal suspension, or semi-solid form, and
the sub-capsule can contain granules, pellets, coated granules, or
coated pellets of the antibiotic. The structure, dimensions, and
composition of one or more sub-capsules can be chosen according to
the needs of the patient type for the timing of release and on
their metabolic phenotypes.
In a third preferred embodiment, the solid oral dosage form
includes the structure of a segmented capsule. This segmented
capsule is preferably segmented along its horizontal axis with one
or more dividers to form one or more sub-compartments. The one or
more dividers have the ability to protect one or more active
ingredients on one side of the divider from interacting with one or
more active ingredients on the other side of the divider. The one
or more dividers can be made from the same or similar excipients
comprising the capsule shell, or different excipients. Each capsule
segment can contain at least one different active pharmaceutical
ingredient. By being compartmentalized separately, at least two
different antibiotic active pharmaceutical ingredients are
protected from interacting with at least each other. In a
two-segment capsule embodiment, segment one can contain
enteric-coated proton pump inhibitor granules (e.g., lansoprazole
and/or omeprazole) and powder or coated pellets of clarithromycin,
while segment two can contain amoxicillin as powder or coated
pellets. In this example, the proton pump inhibitor and
clarithromycin are compartmentalized together with at least one
pharmaceutically acceptable excipient ingredient, and separate from
amoxicillin, within the same solid oral dosage form. In a
three-segment capsule embodiment, segment one can contain
clarithromycin powder, compact flakes, granules or coated pellets,
segment two can contain coated pellets of lansoprazole and/or
omeprazole, and segment three can contain amoxicillin powder,
compact flakes, granules, or coated pellets. In this example, all
active pharmaceutical ingredients can be encapsulated independently
from each other within the same solid oral dosage form at least by
being compartmentalized separately from each other.
In third preferred embodiments, these capsule segments can exist as
separate segments that are fused together during manufacture while
maintaining divisions/dividers between them; and/or these separate
capsule segments are encapsulated together within a larger,
outermost capsule shell. The excipients comprising each separate
segment shell may be varied among the segments to allow for
different release rates of active pharmaceutical ingredients (e.g.,
clarithromycin). For example, the segment shell containing
clarithromycin powder may be thicker and comprised of different
excipients than those comprising the thinner segment shell
containing amoxicillin powder. The segment shell containing
clarithromycin powder may be made thicker and/or made to dissolve
more slowly for those patients with slower metabolisms, and made
thinner and/or made to dissolve more quickly for those patients
with faster metabolisms. A four-segment capsule embodiment can
contain a third antibiotic, such as tetracycline (e.g., 125 mg to
250 mg), in a fourth segment to the solid oral dosage form. Or,
this fourth segment can optionally include other active
pharmaceutical ingredients.
In a fourth preferred embodiment, the solid oral dosage form
includes the structure of a tablet. The tablet can be tableted from
amoxicillin powder, fillers, coated proton pump inhibitor granules,
and clarithromycin either as multiple coated granules, or one or
more large coated pellets or coated sub-tablets within the primary
tablet. Amoxicillin is unable to interact with clarithromycin and
proton pump inhibitor because of their protective coatings in this
unique tablet.
In a fifth preferred embodiment, the solid oral dosage form
includes the structure of a multi-layer tablet. Each layer contains
its own protective coating so that the tablet is also a
multi-coated tablet. Amoxicillin is contained in a separate coated
layer from clarithromycin. The proton pump inhibitor can be
contained in a third coated layer. The structure, dimensions, and
composition of one or more layer coatings can be chosen according
to the needs of the patient type for the timing of release and
their metabolic needs.
In addition to the at least one proton pump inhibitor and at least
two different antibiotics, further alternate embodiments of the
preferred embodiments include at least one additional type of
active pharmaceutical ingredient including, but not limited to, a
beta-lactamase inhibitor, a bismuth compound, and/or a histamine
H2-receptor antagonist. Bismuth compounds can have weak antacid
properties and temporarily help reduce discomforts from irritated
tissue lining the gastrointestinal tract by coating them. The solid
oral dosage form according to the invention can therefore further
include at least one beta-lactamase inhibitor selected from the
class of beta-lactamase inhibitors including, but not limited to,
clavulanic acid, tazobactam, sulbactam, and any salts, solvates,
polymorphs, racemic mixtures, enantiomers, derivatives, mixtures
and combinations thereof; and/or, the solid oral dosage form can
further include at least one bismuth pharmaceutical active
ingredient selected from the class of bismuth compounds including,
but not limited to, bismuth subcitrate, bismuth aluminate, bismuth
oxide, bismuth salicylate, bismuth subgallate, bismuth tannate,
bismuth phosphate, bismuth tribromphenate, bismuth subcarbonate,
bismuth subnitrate, and any salts, solvates, polymorphs, racemic
mixtures, enantiomers, derivatives, mixtures and combinations
thereof; and/or, the solid oral dosage form can further include at
least one histamine H2-receptor antagonist selected from the class
of histamine H2-receptor antagonists including, but not limited to,
ranitidine, cimetidine, famotidine, nizatidine, and any salts,
solvates, polymorphs, racemic mixtures, enantiomers, derivatives,
mixtures and combinations thereof. For example, the third preferred
embodiment of the solid oral dosage form having the structure of a
segmented capsule, as described above, can include an optional
fourth segment that includes at least one pharmaceutically
acceptable excipient ingredient and either a beta-lactamase
inhibitor, a bismuth compound, or a histamine H2-receptor
antagonist as an active pharmaceutical ingredient, instead of, or
in addition to, tetracycline; the other three segments containing
clarithromycin powder, lansoprazole granules and/or omeprazole
granules, and amoxicillin powder, respectively, along with their
respective excipient ingredients.
In most embodiments, said antibiotic active pharmaceutical
ingredient is encapsulated together with at least one
pharmaceutically acceptable excipient ingredient, and together are
independently encapsulated from said at least one other antibiotic
active pharmaceutical ingredient within same said solid oral dosage
form. Pharmaceutically acceptable excipient ingredients can also
help protect against heat, light and ultra-violet light, oxidation,
and moisture. The choice of excipients can also influence the
release rates of active pharmaceutical ingredients and help provide
differential or controlled release rates. Still in other
embodiments, this antibiotic active pharmaceutical ingredient can
be encapsulated together with at least one other active
pharmaceutical ingredient, and together are independently
encapsulated from said at least one other antibiotic active
pharmaceutical ingredient within same said solid oral dosage form.
In these other embodiments, this antibiotic active pharmaceutical
ingredient can be encapsulated together with a proton pump
inhibitor, a beta-lactamase inhibitor, a bismuth compound, or even
a histamine H2-receptor antagonist. However, it is often preferable
to encapsulate the antibiotic ingredient separately from another
active pharmaceutical ingredient, to safeguard against their
interaction, as well. Therefore, said at least one of said at least
two different antibiotic active pharmaceutical ingredients is
preferably further encapsulated independently from said at least
one proton pump inhibitor active pharmaceutical ingredient, or
other type of active pharmaceutical ingredient, within same said
solid oral dosage form.
The solid oral dosage form for the treatment of patients with at
least one of Helicobacter pylori infection and duodenal ulcer
disease includes at least one proton pump inhibitor active
pharmaceutical ingredient; at least two different antibiotic active
pharmaceutical ingredients; and preferably, at least one
pharmaceutically acceptable excipient ingredient, including coating
excipients; and optionally at least one active pharmaceutical
ingredient selected from beta-lactamase inhibitors, bismuth
compounds, and/or histamine H2-receptor antagonists. Of the at
least two different antibiotic active pharmaceutical ingredients of
this solid oral dosage form, at least one of said at least two
different antibiotic active pharmaceutical ingredients is
encapsulated independently from said at least the other antibiotic
active pharmaceutical ingredient of said at least two different
antibiotic active ingredients in order to have at least one of
improved stability, longer shelf-life, maintained potency, less
impurities, and lower toxicity; and/or in order to have a different
release rate. A structure, dimensions, and composition of said
independent encapsulation within same said solid oral dosage form
can be further chosen according to the metabolizing
needs/metabolizing enzyme polymorphisms of a patient/patient group.
The solid oral dosage form preferably includes the structure of a
capsule. The contents interior to the capsule shell preferably
include at least one proton pump inhibitor active pharmaceutical
ingredient in the form of coated granules and/or coated pellets and
selected from lansoprazole and/or dexlansoprazole and/or
omeprazole. The contents interior to the capsule shell also
preferably include amoxicillin and clarithromycin, whereby at least
one of amoxicillin and clarithromycin are encapsulated
independently from the other by either having protective coatings
in the form of coated granules and/or coated pellets, and/or are
compartmentalized separately from the other by being placed and
contained in a separate sub-capsule within same said solid oral
dosage form, to at least protect against their interaction at least
before oral administration.
Importantly, the invention includes methods for the treatment of
patients with at least one of Helicobacter pylori infection and
duodenal ulcer disease.
The invention includes a method for the treatment of patients with
at least one of Helicobacter pylori infection and duodenal ulcer
disease, which comprises orally administering, or the oral
administration of, a solid oral dosage form at least once per day
for at least one week. This solid oral dosage form comprises or
consists of a bismuth-free pharmaceutical formulation; said
bismuth-free pharmaceutical formulation consisting of one
enteric-coated proton pump inhibitor active pharmaceutical
ingredient wherein the one enteric-coated proton pump inhibitor is
optionally in the form of enteric-coated granules or enteric-coated
pellets within same said oral dosage form; one histamine
H2-receptor antagonist active pharmaceutical ingredient, or a
combination thereof. This bismuth-free pharmaceutical formulation
further consists of at least one pharmaceutically acceptable
excipient ingredient and at least two different antibiotic active
pharmaceutical ingredients, wherein said at least two different
antibiotic active pharmaceutical ingredients are selected from the
group consisting of macrolide antibiotics and beta-lactam
antibiotics and wherein at least one of said at least two different
antibiotic active pharmaceutical ingredients is provided with a
layer or covering; coated independent from (or encapsulated
independent from), and protected from contact or interacting with,
at least one other antibiotic active pharmaceutical ingredient of
said bismuth-free pharmaceutical formulation at least before orally
administering the solid oral dosage form and wherein the solid oral
dosage form optionally further consists of at least one
beta-lactamase inhibitor and optionally wherein all active
pharmaceutical ingredients are protected from contact and
interacting with each other within same solid oral dosage form.
In this method, the at least one pharmaceutically acceptable
excipient ingredient is selected from the group consisting of
antiadherents, binders, coatings, capsule shell-comprising
excipients, nanoparticles, chelators, buffering agents, acid
reacting excipients, alkaline reacting excipients, disintegrants,
fillers, diluents, colors, lubricants, glidants, preservatives,
sorbents, flavors, sweeteners, carriers, solvents, surfactants, and
any mixtures and combinations thereof.
In this method, the one enteric-coated proton pump inhibitor active
pharmaceutical ingredient is selected from the group consisting of
lansoprazole, omeprazole, omeprazole magnesium, aripiprazole,
dexlansoprazole, esomeprazole, esomeprazole magnesium, esomeprazole
sodium, esomeprazole strontium, pantoprazole, pantoprazole sodium,
rabeprazole, rabeprazole sodium, and any salts, solvates,
polymorphs, racemic mixtures and enantiomers thereof.
In this method, the at least two different antibiotic active
pharmaceutical ingredients are selected from the group consisting
of clarithromycin, erthythromycin, azithromycin, dirithromycin,
roxithromycin, telithromycin, carbomycin A, josamycin, kitasamycin,
midecamycin, oleandomycin, solithromycin, spiramycin,
troleandomycin; penicillin drugs, amoxicillin, ampicillin,
talampicillin, bacampicillin, lenampicillin, mezlocillin,
sultamicillin, temocillin; and any salts, solvates, polymorphs,
racemic mixtures and enantiomers, mixtures and combinations
thereof.
In this method, at least one of said at least two different
antibiotic active pharmaceutical ingredients is replaced by or
supplemented with a fluoroquinolone antibiotic or tetracycline
antibiotic. For example, if patients develop resistance to an
antibiotic, such as clarithromycin, one or more fluoroquinolone
antibiotics, e.g., levofloxacin, moxifloxacin, or a tetracyline
antibiotic may be needed to replace or supplement clarithromycin in
the solid oral dosage form or outside the solid oral dosage
form.
In this method, the at least one beta-lactamase inhibitor is
selected from the group consisting of clavulanic acid, tazobactam,
sulbactam, and any salts, solvates, polymorphs, racemic mixtures
and, enantiomers, mixtures and combinations thereof.
This method further comprises the step of pharmacogenomic testing
of drug metabolism enzymes of said patients prior to said orally
administering the solid oral dosage form. This would generally
include the pharmacogenomic testing of patients' cytochromes to
determine if they are homozygous extensive metabolizers,
heterozygous extensive metabolizers, or poor metabolizers for one
or more active pharmaceutical ingredients in said solid oral
formulation. Such testing looks at phenotypic variants of genes
that express patients' cytochromes, and can employ the method and
use of genetic sequencing, probing, or duplicating patients' DNA
samples. This method would include a physician prescribing a
formulation of the solid oral dosage form that is best compatible
with said patients.
In this method, the one histamine H2-receptor antagonist is
selected from the group consisting of ranitidine, cimetidine,
famotidine, nizatidine, and any salts, solvates, polymorphs,
racemic mixtures and enantiomers thereof.
In this method, the solid oral dosage form consists of a single
tablet or single capsule structure, although other forms and
structures are possible, including capsules and sub-capsules and
tablets and sub-tablets, and other layers and compartmentalization
arrangements.
In this method, the solid oral dosage form consists of at least two
identical capsules or tablets.
In this method, the solid oral dosage form consists of three to
eight identical capsules or tablets, orally administered as an at
least one dose per day. Up to eight identical capsules or tablets
may be needed to reduce the size of said identical capsules or
tablets for pediatric, elderly, or disabled patients. The reduced
size of said identical capsules or tablets will allow for easier
swallowing in such patients and is meant to improve patient
compliance in those instances, rather than increase the number of
capsules or tablets which would otherwise reduce patient
compliance.
This method includes orally administering the solid oral dosage
form at least twice per day for up to three weeks, preferably
before breakfast and dinner.
This method includes orally administering the solid oral dosage
form twice per day for two weeks.
This method includes orally administering the solid oral dosage
form twice per day for less than two weeks.
The method further comprises the step of gastrointestinal endoscopy
prior to beginning said orally administering said solid oral dosage
form to identify Helicobacter pylori infection or duodenal ulcer
disease. This can involve a rapid urease test, biopsy and tissue
analysis, and growing and assaying microbiological samples.
Likewise, the method further comprises the step of gastrointestinal
endoscopy after completing said orally administering said solid
oral dosage form to confirm elimination of Helicobacter pylori
infection.
In this method, the patients' duodenal ulcer disease is active or
was at least active within the past twelve months.
The method further comprises the step of orally administering an
antibiotic-free pharmaceutical preparation consisting of proton
pump inhibitor active pharmaceutical ingredient, histamine
H2-receptor antagonist active pharmaceutical ingredient,
bismuth-containing active pharmaceutical ingredient, or a
combination thereof after completing all said orally administering
of said solid oral dosage form. By treating said infection with the
antibiotic-containing, solid oral dosage form, an antibiotic-free
pharmaceutical preparation may then be orally administered for
reducing peptic secretion, painful symptoms, and or allowing ulcers
to continue to heal after the infection is gone.
In this method, the at least one of said at least two different
antibiotic active pharmaceutical ingredients is coated
independently or separated from contact with said at least one
other antibiotic active pharmaceutical ingredient of said at least
two different antibiotic active ingredients in order to have at
least one of improved stability, longer shelf-life, maintained
potency, less impurities, lower toxicity, or a combination thereof.
Ideally, all active pharmaceutical ingredients are protected from
contact and interacting with each other within same solid oral
dosage form.
In this method, the at least one of said at least two different
antibiotic active pharmaceutical ingredients is coated
independently from said at least one other antibiotic active
pharmaceutical ingredient of said at least two different antibiotic
active ingredients in order to have a different release rate.
In this method, the at least one of said at least two different
antibiotic active pharmaceutical ingredients is coated
independently from said at least one other antibiotic active
pharmaceutical ingredient of said at least two different antibiotic
active ingredients; a structure, dimensions, and composition of
said independent coating within same said solid oral dosage form
chosen according to the metabolizing needs/metabolizing enzyme
polymorphisms of a patient/patient group in order to provide a
release rate and onset of bioavailability directly proportionate to
the extent of metabolic efficiency of said patient/patient group
with a faster release and onset of bioavailability of said at least
one of said at least two different antibiotic active pharmaceutical
ingredients for heterozygous extensive metabolizers than for poor
metabolizers, and with a faster release and onset of
bioavailability of said at least one of said at least two different
antibiotic active pharmaceutical ingredients for homozygous
extensive metabolizers than for heterozygous extensive
metabolizers.
The invention also includes a method for the treatment of patients
with at least one of Helicobacter pylori infection and duodenal
ulcer disease, said method comprising orally administering a solid
oral dosage form at least once per day for at least one week. This
solid oral dosage form consists of two to eight identical capsules
or tablets that are bismuth-free. These two to eight identical
capsules or tablets consist of one enteric-coated proton pump
inhibitor active pharmaceutical ingredient, one histamine
H2-receptor antagonist active pharmaceutical ingredient, or a
combination thereof. These two to eight identical capsules or
tablets further consist of at least one pharmaceutically acceptable
excipient ingredient, and at least two different antibiotic active
pharmaceutical ingredients, wherein said at least two different
antibiotic active pharmaceutical ingredients are selected from
macrolide antibiotics and beta-lactam antibiotics and wherein at
least one of said at least two different antibiotic active
pharmaceutical ingredient is protected from contact or interacting
with at least one other antibiotic active pharmaceutical ingredient
at least before orally administering the solid oral dosage form by
being coated independent from said at least one other antibiotic
active pharmaceutical ingredient of said at least two different
antibiotic active ingredients within each of said two to eight
identical capsules or tablets and optionally wherein said one
enteric-coated proton pump inhibitor active pharmaceutical
ingredient is in the form of coated granules, coated pellets, or a
combination thereof.
In this method, the one enteric-coated proton pump inhibitor active
pharmaceutical ingredient is in the form of coated granules, coated
pellets, or a combination thereof and selected from the group
consisting of lansoprazole, dexlansoprazole, omeprazole,
aripiprazole, esomeprazole, pantoprazole, and rabeprazole, said one
enteric-coated proton pump inhibitor active pharmaceutical
ingredient is in the amount of 10 mg to 60 mg in said solid oral
dosage form; and said one histamine H2-receptor antagonist is
selected from the group consisting of ranitidine, cimetidine, and
nizatidine in the amount of 150 mg to 800 mg or famotidine in the
amount of 20 mg to 40 mg, in said solid oral dosage form.
The invention also includes a method for the treatment of patients
with at least one of Helicobacter pylori infection and duodenal
ulcer disease, said method comprises orally administering a solid
oral dosage form twice per day for one to two weeks; said solid
oral dosage form consisting of two to six identical single capsules
that are bismuth-free, said two to six identical single capsules
consisting of one enteric-coated proton pump inhibitor active
pharmaceutical ingredient, wherein said one enteric-coated proton
pump inhibitor active pharmaceutical ingredient is selected from
lansoprazole, dexlansoprazole, and omeprazole in an amount of 20 mg
to 30 mg in said solid oral dosage form. These two to six identical
single capsules further consist of at least one pharmaceutically
acceptable excipient ingredient, and at least two different
antibiotic active pharmaceutical ingredients; wherein at least one
of said at least two different antibiotic active pharmaceutical
ingredient is protected from contact or interacting with at least
one other antibiotic active pharmaceutical ingredient at least
before orally administering the solid oral dosage form by being
coated independent from said at least one other antibiotic active
pharmaceutical ingredient of said at least two different antibiotic
active ingredients within each of said two to six identical single
capsules, said at least two different antibiotic active
pharmaceutical ingredients consisting of amoxicillin and
clarithromycin each in an amount of at least 500 mg in said solid
oral dosage form.
The invention also includes a method for the treatment of patients
with at least one of Helicobacter pylori infection and duodenal
ulcer disease, said method comprising orally administering a solid
oral dosage form at least once per day for at least one week. The
solid oral dosage form consists of two to eight identical single
capsules or tablets that are bismuth-free; said two to eight
identical single capsules or tablets consist of one enteric-coated
proton pump inhibitor active pharmaceutical ingredient in the form
of coated granules, coated pellets, or a combination thereof, one
histamine H2-receptor antagonist active pharmaceutical ingredient,
or a combination thereof. These two to eight identical single
capsules or tablets further consist of at least one
pharmaceutically acceptable excipient ingredient and at least two
different antibiotic active pharmaceutical ingredients; wherein
said at least two different antibiotic active pharmaceutical
ingredients are selected from the group consisting of macrolide
antibiotics and beta-lactam antibiotics and wherein at least one of
said at least two different antibiotic active pharmaceutical
ingredients is protected from contact or interacting with at least
one other antibiotic active pharmaceutical ingredient at least
before orally administering the solid oral dosage form by being
coated independent from said at least one other antibiotic active
pharmaceutical ingredient within each of said two to eight
identical single capsules or tablets in order to have at least one
of a different release rate, improved stability, longer shelf-life,
maintained potency, less impurities, lower toxicity, or a
combination thereof; a coated form of said at least one of said at
least two different antibiotic active pharmaceutical ingredients
having a structure, dimensions, and composition chosen according to
the metabolizing needs/metabolizing enzyme polymorphisms of a
patient/patient group in order to provide a release rate and onset
of bioavailability directly proportionate to the extent of
metabolic efficiency of said patient/patient group with a faster
release and onset of bioavailability of said at least one of said
at least two different antibiotic active pharmaceutical ingredients
for heterozygous extensive metabolizers than for poor metabolizers,
and with a faster release and onset of bioavailability of said at
least one of said at least two different antibiotic active
pharmaceutical ingredients for homozygous extensive metabolizers
than for heterozygous extensive metabolizers; and wherein all
active pharmaceutical ingredients are protected from contact and
interacting with each other within same said solid oral dosage
form.
In this method, the one enteric-coated proton pump inhibitor active
pharmaceutical ingredient in the form of coated granules, coated
pellets, or a combination thereof is selected from the group
consisting of lansoprazole, dexlansoprazole, and omeprazole in an
amount of 20 mg to 30 mg in said solid oral dosage form, and said
at least two different antibiotic active pharmaceutical ingredients
consists of amoxicillin and clarithromycin each in an amount of at
least 500 mg in said solid oral dosage form, wherein at least
clarithromycin is in coated form in said solid oral dosage
form.
Choice and amounts of pharmaceutically acceptable excipient
ingredients and other methods of use and dosing of the solid oral
formulation, along with other variations and embodiments of the
invention described herein will now be apparent to those of skill
in the art without departing from the disclosure of the invention
or the coverage of the claims to follow.
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